SINGLE USE SYSTEMS IN NEXT-GEN BIOLOGICS DRUG SUBSTANCE MANUFACTURING

Transcription

1 JUNE 21, 2018 SINGLE USE SYSTEMS IN NEXT-GEN BIOLOGICS DRUG SUBSTANCE MANUFACTURING GANESH VEDANTHAM PROCESS DEVELOPMENT

2 MODALITIES IN THE AMGEN PORTFOLIO 2

3 AMGEN IS EVOLVING OPERATIONS CAPABILITIES TO ENABLE DELIVERY OF PROGRESSIVE/MULTI-MODALITY MEDICINES Amgen Strategic Imperatives Outcome Patient Focus Improve patient experience and differentiate products More targeted products Product Heterogeneity Flexible Drug Discovery & Development Expand Global Presence Maintain modality independence Pursue strategic acquisitions Consider Biosimilar opportunities Establish operations in new markets Manage demand uncertainty Meet local SKU profile/requirements Greater Demand Uncertainty Lower Per Product Volume BALANCE USE OF EXISTING FOOTPRINT WITH ADDITION OF NEW CAPABILITIES TO LOWER COSTS, AND INCREASE FLEXIBILITY AND SPEED 3

4 ENABLING FAST AND FLEXIBLE OPERATIONS FOR DRUG SUBSTANCE (DS) Conventional Key Enabling Technologies Flexible SQFT 160K Brx Scale 15,000 L Capital $1B Headcount 700 Single-use bioreactor and purification systems Modular design and construction Inter Connected processing In-line Analytics Remote monitoring and control 4 SQFT Brx Scale 45K 2,000 L Capital $200M Headcount 200 Source of illustrations: Next-Generation Facilities for Monoclonal Antibody Production, N. Guldager, Pharmaceutical Technology (July 2009)

5 WE GAINED APPROVAL OF OUR FIRST NEXT-GEN BIOMANUFACTURING FACILITY IN SINGAPORE IN 2017 Investment enabled us to deploy a Flexible/Reconfigurable facility with substantially agility and efficiency compared to traditional facility Time: 1/2 CapEx: 1/4 OpEx: 1/3 SINGAPORE FACILITY PPQ COMPLETED 29 MONTHS POST LAND ACQUISITION 5

6 DEPLOYING SINGLE USE SYSTEMS FOR NEXT GENERATION BIOMANUFACTURING Qualification Plant PPQ Focus on launch Strong qualification & regulatory submission packages Leak rates for high risk steps Reliability and Efficiency Higher Run Rates Focus on Increasing Run Rate Defect rates with prioritization on reducing leaks Control & communication of changes by suppliers and subsuppliers Speed of issue resolution, nonconformance closure, and drug substance lot release Agility and Differentiation Multi-Product with Faster Innovation Deployment Focus on Speed and Innovation Revision to RM spec that drive process improvements Qual for new and modified SUS Select suppliers that meet requirements for reliability and control as options of second sources of other single use materials Reliability a Focus as well as Key Measures for Future Innovation 6

7 DEPLOYING SINGLE USE SYSTEMS WAS A KEY ENABLER TO OUR FLEXIBLE DESIGN FOR THE INVESTMENT IN AMGEN SINGAPORE Single use bioreactors Single use prep, hold and pool vessels 95% reduction in surface area requiring cleaning Modular No process transfer piping 7

8 DEPLOYING SINGLE-USE TECHNOLOGY: CHALLENGES AND OPPORTUNITIES Traditional Systems go through testing and verification during and after installation Single-Use Systems (SUS) are replaced after use Testing procedures may be detrimental or destructive Dependence on suppliers quality systems and documentation Supply chain transparency Sourcing strategy, change management Focus on design qualification/verification, material and component selection, functional performance Requires robust framework for implementation 8

9 SCIENCE AND RISK-BASED FRAMEWORK WAS APPLIED FOR SINGLE-USE IMPLEMENTATION Based on interpretation and application of: ASTM E3051, ASTM-2500 PDA TR 66 BPOG Single Use Requirement Harmonization ICH Q9 EU Vol. 4 Annex 15 FDA Process Validation Guidance ISPE Baseline Guide Vol. 12: Verification Helped shape the industry approach in single use implementation Focus on critical aspects Use of Good Engineering Practice Expands role of Subject Matter Experts Use of supplier documentation Continuous improvement and change management Quality is designed in upfront rather than tested later 9

10 QUALIFYING EACH SUS WITH A HOLISTIC VIEW OF LEACHABLES/ EXTRACTABLES RISK Approach follows industry standards for leachable and extractable assessments Step 1 Step 2 Step 3 Risk assessment for each material based on vendor and Amgen generated data. Define toxicological threshold of concern (TTC) for identified leachables. Establish leachables content based on cumulative leachable load and process clearances. Toxicology evaluation of E&L data. 10

11 CUMULATIVE LEACHABLES, CLEARANCE, AND TOXICOLOGICAL EVALUATION APPROACH Calculate cumulative leachable levels based on data for bags, tubing, connectors, filters and chromatography resins used in DS Worst-case areas, lengths, sizes, fill volumes were used to calculate a maximum exposure Clearance from flushing prior to processing as well as process clearance across Perfusion, Chromatography, and Diafiltration steps were considered to calculate leachable levels in DS Maximum theoretical leachable level was calculated, which was below the toxicological threshold per dose provided by our Amgen Toxicology Group 11

12 HOLISTIC APPROACH SUMS CUMULATIVE LEACHABLES FROM SOURCES AND ACCOUNTS FOR PROCESS CLEARANCE Mechanisms of clearance 1. Dilution through perfusion volume 2. Bind/elute Chromatography As intermediates bind to the resin, the leachables pass through the column and are reduced prior to subsequent steps 3. Ultrafiltration and Diafiltration As the protein is retained, small molecule leachables pass through the UFDF 30kDa molecular cut off membrane SUB Prod SUB Clearance Steps Media/ Buffer/ Tote 12

13 PROCESS ACCUMULATION AND CLEARANCE CALCULATIONS SHOW AREAS OF RISK FOR CONTRIBUTIONS TO LEACHABLES DS fill is highest contributor to leachables concentrations Low risk of leachables contribution to drug substance for steps upstream of UF/DF Previous experience revealed some cell lines are vulnerable to leachables in cell culture steps upstream of 2000L SUB Wave bioreactor and 500L SUB are highest risk for cell culture impact Accumulated Leachables/Extractables at End of Each Step 13

14 PROGRAMS ARE IN PLACE TO HOLISTICALLY EVALUATE LEACHABLES RISKS FOR SINGLE-USE SYSTEMS The toxicology review derived a parenteral Permitted Daily Exposure (PDE) value of by following the principles and methodologies in ICH Q3C(R5). Toxicological Threshold of Concern set to be several orders of magnitude below the PDE Holistic, cumulative calculation showed that potential leachables are well below the Toxicological Threshold of Concern Process clearance is expected and could be greater than used in calculation Direct testing of drug substance was below the analytical limit of quantification from the leachables study, which is also below the Toxicological Threshold of Concern and the PDE 14

15 CONCLUSIONS Innovation is at the heart of our strategy: Progressive manufacturing and attribute testing technologies into our operations allows for improved speed, cost, and quality control Risk and science-based approaches provided a holistic evaluation to expand application of single use systems Qualifying single use systems robustly is complex, but is no longer our biggest challenge We like to see consistently demonstrated reliability on existing SUS before we commercialize new/innovation SUS with suppliers We need to improve our speed and efficiency at making modifications to existing single use systems and deploying new single use systems 15